New heterocycle-substituted alkylamides

ABSTRACT

Compounds of general formula (I): ##STR1## where R, X, A, B and p are defined in the description. Medicinal products useful for treating sleeping disorders comprising the same.

The present application is a division of our prior-filed copendingapplication Ser. No. 07/848,373, filed Mar. 9, 1992, now U.S. Pat. No.5,240,919, issued Aug. 31, 1993.

The present invention relates to new heterocycle-substitutedalkylamides, to a process for preparing them and to pharmaceuticalcompositions containing them.

Very few heterocycle-substituted alkylamides containing abenzoxazolinone, benzothiazolinone or benzoxazinone unit have beendescribed. Moreover, some benzoxazolinone- orbenzothiazolinone-substituted 2-haloacetamides, described as herbicides,are known (U.S. Pat. Nos. 4,311,858, and 4,258,196).

The Applicant has now discovered new heterocycle-substituted ethylamideswhich possess the property of binding with very high affinity tomelatonin receptors. This feature makes the compounds of the inventionadvantageous in disorders of the central nervous system--in particularas anxiolytics and antipsychotics--and of the cerebral circulation andas analgesics. The compounds of the invention are also capable of beingused as ovulation regulators, as well as in the treatment of somecancers on account of their immunostimulatory properties.

More especially, the invention relates to the compounds of generalformula (I): ##STR2## in which: A represents an oxygen or sulfur atom,

X represents a CH₂ group or a single bond,

R represents:

either a hydrogen atom or a lower alkyl group,

and in this case p=1 and B represents an arrangement --CH₂ --CH₂ --NR₁--CO--R₂ where R₁ represents a hydrogen atom or a linear or branchedlower alkyl group,

and R₂ represents:

a hydrogen atom,

a cycloalkyl or linear or branched lower alkyl group, optionallysubstituted with a halogen atom,

a cycloalkyl group substituted with a linear or branched lower alkylgroup,

an aryl or heteroaryl or aryl(lower alkyl) or substituted aryl orsubstituted heteroaryl or substituted arylalkyl group, on theunderstanding that heteroaryl group is understood to mean pyridyl orindoyl

a group of formula: ##STR3## G representing a linear or branched loweralkyl group, R₃ and R₄, which may be identical or different, eachrepresent a lower alkyl group or a hydrogen atom or a phenyl orphenyl(lower alkyl) group, or R₃ and R₄, with the nitrogen atom to whichthey are attached, form a mono- or bicyclic, aromatic or non-aromaticheterocyclic system optionally comprising another hetero atom chosenfrom nitrogen, oxygen or sulphur and optionally substituted with one ormore lower alkyl or oxo, aryl or aryl(lower alkyl), or substituted arylor substituted aryl(lower alkyl) groups, on the understanding that, inthe definitions of R₂, R₃ and R₄, the term substituted qualifying aryland arylalkyl and heteroaryl groups means that these groups aresubstituted with one or more radicals chosen from lower alkyl, loweralkoxy, trifluoromethyl or halogen atom,

or alternatively R₁, with R₂ and the group N--CO, forms a heterocyclicsystem of formula: ##STR4## ·with J being a linear or branched alkylradical comprising from 2 to 8 carbon atoms,

or an arrangement (CH₂)₂ --NR₁ --CO--R₂ with R₁ and R₂ having the samedefinition as above, and in this case p equals 0 or 1 and B represents alower alkoxy group,

where appropriate their isomers, epimers and diastereoisomers as wellas, where appropriate, their addition salts with a pharmaceuticallyacceptable acid or base, on the understanding that lower alkyl and loweralkoxy mean groups comprising from 1 to 6 carbon atoms and thatcycloalkyl means groups comprising from 3 to 8 carbon atoms.

Among pharmaceutically acceptable acids which can, where appropriate, beadded to the compounds of formula (I) to obtain a salt, hydrochloric,sulfuric, tartaric, maleic, fumaric, oxalic, methanesulfonic andcamphoric acids, and the like, may be mentioned without impliedlimitation.

Among pharmaceutically acceptable bases which can, where appropriate, beadded to the compounds of formula (I) to obtain a salt, sodium,potassium, calcium or aluminum hydroxides, alkali metal or alkalineearth metal carbonates or organic bases such as triethylamine,benzylamine, diethylamine, tert-butylamine, dicyclohexylamine, arginine,and the like, may be mentioned without implied limitation.

The subject of the present invention is also the process for preparingthe compounds of formula (I), wherein:

when B is other than an arrangement --CH₂ --CH₂ NR₁ COR₂, a compound offormula (II): ##STR5## in which A, B, p and X have the same definitionas in the formula (I) except for the case where B represents an .arrangement --CH₂ --CH₂ --NR₁ COR₂, is used as starting material, whichcompound is treated with an alkali metal agent to obtain a compound offormula (III): ##STR6## which is treated: either with a compound offormula (IV/A):

    Hal (CH.sub.2).sub.2 Halo                                  (IV/A)

where Hal and Halo, which may be identical or different, represent ahalogen atom,

to obtain a compound of formula (V/A): ##STR7## in which A, X, B, p andHalo have the same meaning as above,

which is treated with an amine of formula HNR₁ where R₁ has the samedefinition as in the formula (I), to obtain a compound of formula (VI):##STR8## in which A, B, p, R₁ and X have the same definition as above,or with a compound of formula (IV/B):

    HalCH.sub.2 CN                                             (IV/B)

in which Hal has the same meaning as above,

to obtain a compound of formula (V/B): ##STR9## in which X, A, B and phave the same meaning as above, which compound of formula (V/B) issubjected to a reducing agent and then, when R₁ represents a lower alkylgroup in the compound of formula (I) which it is desired to obtain, toan alkylating agent, to obtain a compound of formula (VI) as definedabove,

which compound of formula (VI) is treated:

either with a compound of formula (VII): ##STR10## in which E denotes aleaving group chosen from hydroxyl, lower alkoxy or halogen, G, R₃ andR₄ having the same meaning as in the formula (I), optionally in thepresence of an alkaline agent, to yield a compound of formula (I/A), aspecial case of the compounds of formula (I): ##STR11## in which A, B,X, R₁, R₃, R₄, G and p have the same definition as above,

R₂ here denoting a group: ##STR12## on condition that B does notrepresent a group:

    --CH.sub.2 --CH.sub.2 NR.sub.1 --COR.sub.2

which is purified, if so desired, by conventional techniques such aschromatography or crystallization and which is salified, if so desired,with a pharmaceutically acceptable acid,

or with an acid chloride of formula (IX):

    Cl--CO--R'.sub.2                                           (IX)

or with the corresponding acid anhydride,

R'₂ here denoting:

a cycloalkyl or linear or branched lower alkyl group optionallysubstituted with a halogen atom, or a cycloalkyl group substituted witha linear or branched lower alkyl group,

an aryl or heteroaryl or aryl(lower alkyl) group optionally substitutedwith one or more halogen atoms or groups chosen from lower alkyl, loweralkoxy or trifluoromethyl, the term heteroaryl having the same meaningas above,

to yield a compound of formula (I/B): ##STR13## a special case of thecompounds of formula (I) in which m, X, A, B, p, R₁ and R'₂ have thesame definition as above, it not being possible for B to represent anarrangement --CH₂ --CH₂ --NR₁ COR₂,

which is purified, if necessary, by conventional techniques such aschromatography and/or crystallization,

which compound of formula (I/B), in the case where R'₂ represents alinear or branched lower alkyl group substituted with a halogen atom,may be subjected, if so desired, to the action of an amine of formula(X): ##STR14## in which R₃ and R₄ have the same definition as above, inexcess or in the presence of a tertiary amine or an alkali metal salt,to yield a compound of formula (I/A) as defined above, which, if sodesired, is purified by a conventional technique such as chromatographyand/or crystallization, and/or salified with a pharmaceuticallyacceptable acid,

which compound of formula (I/B), when R'₂ represents a linear orbranched alkyl substituent comprising at least two carbon atoms andsubstituted with a halogen atom, and when R₁ simultaneously represents ahydrogen atom, may be subjected, if so desired, to the action of astrong base and preferably an alkali metal alcoholate to yield acompound of formula (I/C): ##STR15## in which B, p, X and A have thesame meaning as above, on the understanding that B cannot represent agroup --CH₂ --CH₂ NRCOR₂ and J represents a linear or branched alkylgroup comprising from 2 to 8 carbon atoms, a special case of thecompounds of formula (I) for which R₁ and R₂ with NCO form a monocyclicsystem substituted with an oxo group and optionally substituted with oneor more lower alkyl groups,

which is purified, if so desired, by a technique chosen fromcrystallization or chromatography,

when B represents an arrangement --CH₂ --CH₂ NR₁ COR₂ and p represents1,

a compound of formula (VIII): ##STR16## which R₁, R, X and A have thesame definition as in the formula (I), these compounds being describedin Patent Application FR 90/11,866 (corresponding to U.S. Ser. No.07/765,959, filed Sep. 26, 1991, now U.S. Pat. No. 5,196,434, issuedMar. 23, 1993), and in U.S. Pat. Nos. 4,554,284 and 4,558,060, is usedas starting material,

which compound is treated:

either with a compound of formula (VII): ##STR17## in which E denotes aleaving group chosen from hydroxyl, lower alkoxy or halogen, G, R₃ andR₄ having the same meaning as in the formula (I), optionally in thepresence of an alkaline agent, to yield a compound of formula (I/D), aspecial case of the compounds of formula (I): ##STR18## in which X andA, R₁, R₃, R₄ and G have the same definition as above and R represents ahydrogen atom or a lower alkyl group,

R₂ here denoting a group: ##STR19## which is purified, if so desired, byconventional techniques such as chromatography and/or crystallizationand which is salified, if so desired, with a pharmaceutically acceptableacid or, when R represents a hydrogen atom, with a pharmaceuticallyacceptable base,

or with an acid chloride of formula (IX):

    Cl--CO--R'.sub.2                                           (IX)

or with the corresponding acid anhydride,

R'₂ here denoting:

a cycloalkyl or linear or branched lower alkyl group optionallysubstituted with a halogen atom, or a cycloalkyl group substituted witha linear or branched lower alkyl group,

an aryl or heteroaryl or aryl(lower alkyl) group optionally substitutedwith one or more halogen atoms or groups chosen from lower alkyl, loweralkoxy or trifluoromethyl, the term heteroaryl having the same meaningas above,

to yield a compound of formula (I/E): ##STR20## a special case of thecompounds of formula (I) in which R₁, X, A and R'₂ have the samedefinition as above and R represents a lower alkyl group or a hydrogenatom,

which is purified, if necessary, by conventional techniques such aschromatography and/or crystallization and which is salified, if sodesired, with a pharmaceutically acceptable base when R represents ahydrogen atom,

which compound of formula (I/E), in the case where R'₂ represents alinear or branched lower alkyl group substituted with a halogen atom,may be subjected, if so desired, to the action of an amine of formula(X): ##STR21## in which R₃ and R₄ have the same definition as above, inexcess or in the presence of a tertiary amine or an alkali metal salt,to yield a compound of formula (I/D) as defined above, which, if sodesired, is purified by a conventional technique such as chromatographyand/or crystallization, and/or salified with a pharmaceuticallyacceptable acid,

which compound of formula (I/E), when R'₂ represents a linear orbranched alkyl substituent comprising at lest two carbon atoms andsubstituted with a halogen atom, and when R₁ simultaneously represents ahydrogen atom, may be subjected, if so desired, to the action of astrong base and preferably an alkali metal alcoholate to yield acompound of formula (I/F): ##STR22## in which R represents a hydrogenatom or a lower alkyl group, X and A have the same meaning as above andJ represents a linear or branched alkyl group comprising from 2 to 8carbon atoms, a special case of the compounds of formula (I) for whichR₁ and R₂ with NCO form a monocyclic system substituted with an oxogroup and optionally substituted with one or more lower alkyl groups,

which is purified, if so desired, by a technique chosen fromcrystallization or chromatography and which is salified, if so desired,when R represents a hydrogen atom, with a pharmaceutically acceptablebase.

The products of formula (VI) are new and form part of the invention onthe same basis as the products of formula (I), for which they constitutesynthesis intermediates, except for the compounds for which:

X represents a single bond,

A represents a sulfur atom and p represents 0.

The products of formulae (V/A) and (V/B) for which p is other than 0 arealso new, and also form part of the invention on the same basis as theproducts of formula (I), for which they constitute synthesisintermediates.

Another special case relates to the compounds of formula (I/K):##STR23## which is obtained in a single step by catalytic reduction ofthe compounds of formula (V/K) in an acetic anhydride medium: ##STR24##followed, if necessary, by purification and, R₁ represents a lower alkylgroup, by treatment with an alkylating agent.

The compounds of formula (I) possess advantageous pharmacologicalproperties.

A pharmacological study of the compounds of the invention showed, ineffect, that they are of low toxicity and endowed with appreciableaffinity for melatonin receptors, and that, in addition, theysubstantially increase melatonin synthesis by the pineal gland.Furthermore, they possess considerable activity in relation to thecentral nervous system and, in particular, sedative, anxiolytic,antipsychotic and analgesic properties as well as effects on themicrocirculation have been noted, these enabling it to be establishedthat the products of the invention are useful in the treatment ofstress, sleep disorders, anxiety, seasonal depression, insomnia andfatigue due to jet lag, schizophrenia, panic attacks, melancholia,appetite regulation, insomnia, psychotic disorders, epilepsy,Parkinson's disease, senile dementia, the various disorders linked tonormal or pathological aging, migraine, memory loss, Alzheimer's diseaseand also disorders of the cerebral circulation.

In another sphere of activity, it is apparent that the products of theinvention possess ovulation-inhibiting properties, and immunomodulatoryproperties and that they are hence capable of being used in thetreatment of certain cancers, and that, when administered externally,they are useful in the treatment of psoriasis, acne and seborrhea,protect the skin and promote hair growth. They can also have aveterinary application owing to their effect on the coat.

The subject of the present invention is also pharmaceutical compositionscontaining the products of formula (I) or, where appropriate, one oftheir addition salts with a pharmaceutically acceptable acid, alone orin combination with one or more pharmaceutically acceptable, non-toxic,inert excipients or vehicles.

Among the pharmaceutical compositions according to the invention, theremay be mentioned, more especially, those which are suitable for oral,parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular orrespiratory administration, and in particular simple or sugar-coatedtablets, sublingual tablets, sachets, packets, hard gelatin capsules,sublingual preparations, troches, suppositories, creams, ointments, skingels, ampuls for oral use or injection, and the like.

The dosage varies according to the patient's age and weight, theadministration route and the nature of the therapeutic indication or ofany associated treatments, and ranges between 0.1 mg and 1 gram per 24hours.

The examples which follow illustrate the invention but in no way limitit.

EXAMPLE 1 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]ACETAMIDE STAGE A(6-METHOXY-3-BENZOXAZOLINONYL)ACETONITRILE

0.1 gram-atom of sodium is added in small pieces with magnetic stirringinto a 250-cm³ round-bottomed flask containing 100 cm³ of absoluteethanol.

The mixture is left stirring until the sodium has dissolved completely.0.1 mol of 6-methoxybenzoxazolinone is added, stirring is continued for30 minutes and the mixture is then taken to dryness.

The sodium derivative obtained is solubilized in 80 cm³ of anhydrousdimethylformamide. With magnetic stirring, 0.12 mol ofchloroacetonitrile is added via a dropping funnel. The reaction mixtureis heated to 80° C. for 1 hour 30 minutes. It is allowed to cool andthen poured into 400 cm³ of ice-cold water.

The precipitate formed is drained, washed until the washing liquors areneutral, dried and recrystallized.

Recrystallization solvent: 95° strength alcohol

Yield: 95%

Melting point: 142-143° C.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 58.82        3.95   13.72                                         Found:      58.73        3.82   13.69                                         ______________________________________                                        Infrared spectrometry:                                                        (3060-2940) cm.sup.-1, C--H                                                   1770 cm.sup.-1, ν CO(O--CO--N)                                             1630 cm.sup.-1, ν C═C (aromatic)                                       Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         3.85 ppm, (s, 3H), OCH.sub.3                                                  4.75 ppm, (s, 2H), CH.sub.2 --CN                                              6.80 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.6                            7.05 ppm, (d, 1H), H.sub.7                                                    ______________________________________                                    

STAGE B 2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYLAMINE HYDROCHLORIDE

In a round-bottomed flask, 0.03 mol of(6-methoxy-3-benzoxazolinonyl)acetonitrile is dissolved with magneticstirring in 50 cm³ of tetrahydrofuran at room temperature.

0.05 mol of methylborane sulfide is added slowly under a nitrogenatmosphere using a dropping funnel. The mixture is heated to reflux for30 minutes. It is cooled in an ice bath, and 30 cm³ of 6N hydrochloricacid solution are then added very slowly. The mixture is heated toreflux for 30 minutes.

It is allowed to cool, and the precipitate formed is drained, washedwith 30 cm³ of acetone, dried and recrystallized in a suitable solvent.

Recrystallization solvent: 95° strength alcohol

Yield: 83% .

Melting point:>260° C.

    ______________________________________                                        Infrared spectrometry:                                                        (3120-2500) cm.sup.-1, ν NH.sub.2 salt                                     1770 cm.sup.-1, ν CO(OCON)                                                 (1635-1620) cm.sup.-1, ν CC (aromatic)                                     Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                          ##STR25##                                                                    3.75 ppm, (s, 3H), OCH.sub.3                                                   ##STR26##                                                                    6.82 ppm, (dd, 1H), H.sub.5                                                   7.00 ppm, (d, 1H), H.sub.7                                                    7.40 ppm, (d, 1H), H.sub.4                                                    8.40 ppm, (signal, 2H), NH.sub.2 disappears in D.sub.2 O                      ______________________________________                                    

STAGE C N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]ACETAMIDE

0.02 mol of 3-(2-aminoethyl)-6-methoxybenzoxazolinone hydrochloride isdissolved in a water/chloroform mixture. 0.02 mol of potassium carbonateis added and the mixture is left stirring for 1 hour.

It is cooled in an ice bath, and 0.022 mol of acetyl chloride is thenadded slowly. The mixture is kept stirring for 1/2 hour. The chloroformphase is taken to dryness, and for the residue is then recrystallized ina suitable solvent.

Recrystallization solvent: Absolute alcohol.

Yield: 86%.

Melting point: 162-164° C.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 57.59        5.64   11.20                                         Found:      57.30        5.54   10.96                                         ______________________________________                                        Infrared spectrometry:                                                        3320 cm.sup.-1, ν NH                                                       (3060-2840) cm.sup.-1, ν CH                                                1765 cm.sup.-1, ν CO(OCON)                                                 1640 cm.sup.-1, ν CO (amide)                                               1620 cm.sup.-1, ν CC (aromatic)                                            Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         1.94 ppm, (s, 3H), COCH.sub.3                                                  ##STR27##                                                                    3.80 ppm, (s, 3H), OCH.sub.3                                                  3.95 ppm, (t, 2H), NCH.sub.2                                                  6.20 ppm, (signal, 1H), NH                                                    6.65 ppm, (unresolved peaks, 2H), H.sub.5, H.sub.7                            6.96 ppm, (d, 1H), H.sub.4                                                    ______________________________________                                    

EXAMPLE 2 N-[2-(5-METHOXY-3-BENZOXAZOLINONYL)ETHYL]ACETAMIDE

Using the procedure described in Example 1, but replacing6-methoxybenzoxazolinone in stage A by 5-methoxybenzoxazolinone, thefollowing are obtained:

STAGE A: (5-METHOXY-3-BENZOXAZOLINONYL)ACETONITRILE

Melting point: 148-149° C.

Yield: 93%.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 58.82        3.95   13.72                                         Found:      58.55        3.71   13.61                                         ______________________________________                                        Infrared spectrometry:                                                        (3060-2900) cm.sup.-1, ν CH                                                1790 cm.sup.-1, ν CO(OCON)                                                 1620 cm.sup.-1, ν CC (aromatic)                                            Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         3.86 ppm, (s, 3H), OCH.sub.3                                                   ##STR28##                                                                    6.70 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.6                            7.20 ppm, (d, 1H), H.sub.7                                                    ______________________________________                                    

STAGE B 2-(5-METHOXY-3-BENZOXAZOLINONYL)ETHYLAMINE HYDROCHLORIDE

Recrystallization solvent: 95° strength alcohol.

Yield: 81%.

Melting point:>260° C.

    ______________________________________                                        Infrared spectrometry:                                                        (3120-2500), ν NH.sub.2 salt                                               1765 cm.sup.-1, ν CO(OCON)                                                 1620 cm.sup.-1, ν CC (aromatic)                                            Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                          ##STR29##                                                                    3.75 ppm, (s, 3H), OCH.sub.3                                                   ##STR30##                                                                    6.70 ppm, (dd, 1H), H.sub.6                                                   (7-7.40) ppm, (unresolved peaks, 2H), H.sub.4, H.sub.7                        9.50 ppm (signal, 2H) NH.sub.2 disappears in D.sub.2 O                        ______________________________________                                    

STAGE C N-[2-(5-METHOXY-3-BENZOXAZOLINONYL)ETHYL]ACETAMIDE

Recrystallization solvent: Toluene.

Yield: 87%.

Melting point: 118-120° C.

Elemental analysis:

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 57.59        5.64   11.20                                         Found:      57.50        5.57   11.26                                         ______________________________________                                        Infrared spectrometry:                                                        3300 cm.sup.-1, ν NH (amide)                                               (3060-2840) cm.sup.-1, ν CH                                                1765 cm.sup.-1, ν CO(OCON)                                                 1655 cm.sup.-1, ν CO (amide)                                               1630 cm.sup.-1, ν CC (aromatic)                                            Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         1.93 ppm, (s, 3H), COCH.sub.3                                                  ##STR31##                                                                    3.80 ppm, (s, 3H), OCH.sub.3                                                  3.94 ppm, (t, 2H), CH.sub.2 N                                                 6.25 ppm, (signal, 1H), NH                                                    6.64 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.6                            7.10 ppm, (d, 1H), H.sub.7                                                    ______________________________________                                    

EXAMPLE 3 N-[2-(5-METHOXY-3-BENZOXAZOLINONYL)ETHYL]ISOBUTYRAMIDE

Using the procedure described in Example 2, stage C, but replacingacetyl chloride by isobutyryl chloride, the product of the title isobtained.

Recrystallization solvent: Toluene/Hexane.

Yield: 82%.

Melting point: 130-131° C.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 60.41        6.52   10.06                                         Found:      60.55        6.66   10.01                                         ______________________________________                                        Infrared spectrometry:                                                        3300 cm.sup.-1, ν N--H                                                     (3080-2840) cm.sup.-1, ν C--H                                              1760 cm.sup.-1, ν CO(O--CO--N)                                             1640 cm.sup.-1, ν CO (amide)                                               1625 cm.sup.-1, ν C═C (aromatic)                                       Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         1.10 ppm, (d, 6H), CH(CH.sub.3).sub.2                                         2.25 ppm, (multiplet, 1H), CH                                                 3.75 ppm, (s, 3H), OCH.sub.3                                                  6.20 ppm, (signal, 1H), NH                                                    6.60 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.6                            7.10 ppm, (d, 1H), H.sub.7)                                                   ______________________________________                                    

EXAMPLE 4 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]ISOBUTYRAMIDE

Using the procedure described in Example 2, stage C, but replacingacetyl chloride by isobutyryl chloride, the product of the title isobtained.

Recrystallization solvent: Toluene.

Melting point: 161-162° C.

Yield: 86%.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 60.41        6.52   10.06                                         Found:      60.36        6.48   10.11                                         ______________________________________                                        Infrared spectrometry:                                                        3300 cm.sup.-1, ν NH                                                       (3080-2840) cm.sup.-1, ν CH                                                1760 cm.sup.-1, ν CO(OCON)                                                 1640 cm.sup.-1, ν CO (amide)                                               1625 cm.sup.-1, ν CC (aromatic)                                            Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                          ##STR32##                                                                    2.25 ppm, (multiplet, 1H), CH                                                 3.60 ppm, (multiplet, 2H), CH.sub.2 NH                                        3.75 ppm, (s, 3H), OCH.sub.3                                                  3.95 ppm, (t, 2H), CH.sub.2 N                                                 6.15 ppm, (signal, 1H), NH                                                    6.65 ppm, (unresolved peaks, 2H), H.sub.5, H.sub.7                            6.95 ppm, (d, 1H), H.sub.4                                                    ______________________________________                                    

EXAMPLE 5 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]PHENYLACETAMIDE

Using the procedure described in Example 2, but replacing acetylchloride by phenacetyl chloride, the product of the title is obtained.

    ______________________________________                                        Infrared spectrometry:                                                        3300 cm.sup.-1, ν N--H                                                     1760 cm.sup.-1, ν CO(O--CO--N)                                             Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         3.75 ppm, singlet, 3H, OCH.sub.3                                              ______________________________________                                    

EXAMPLE 6N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE##STR33##

A mixture of 0.02 ml of 3-(2-aminoethyl)-6-methoxybenzoxazolinone and0.022 mol of methyl (2-oxo-1-pyrrolidinyl)acetate is heated withmagnetic stirring to a temperature of 80° C. for 3 hours. The medium istaken up with slightly acid water and the precipitate is drained.

    ______________________________________                                        Infrared spectrometry:                                                        3300 cm.sup.-1, ν N--H                                                     1760 cm.sup.-1, ν CO(O--CO--N)                                             Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         3.75 ppm, singlet, 3H, OCH.sub.3                                              ______________________________________                                    

EXAMPLE 7 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-4-CHLOROBUTYRAMIDE

Using the procedure described in Example 2, but replacing ethyl acetylchloride by 4-chlorobutyryl chloride, the product of the title isobtained.

Infrared spectrometry

1760 cm⁻¹, νCO(O--CO--N)

Nuclear Magnetic Resonance Spectrometry (CDCl₃)

3.80 ppm, singlet, 3H, OCH₃

EXAMPLE 8 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-PYRROLIDINONE

0.01 gram-atom of sodium is dissolved in 50 cm³ of ethanol.N-[2-(6-Methoxy-3-benzoxazolinonyl)ethyl]-4-chlorobutyramide, obtainedin the preceding example, is added with magnetic stirring. The mixtureis kept stirring for 20 minutes. It is taken to dryness. The residue issolubilized in 40 cm³ of anhydrous dimethylformamide. The mixture isheated to boiling for 7 hours. It is evaporated under vacuum and theresidue is taken up with ether. The mixture is filtered and taken todryness. The product is recrystallized.

Infrared Spectrometry

1760 cm⁻¹, νCO(O--CO--N)

Nuclear Magnetic Resonance Spectrometry (CDCl₃):

3.80 ppm, singlet, 3H, OCH₃

EXAMPLE 9 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-BROMOACETAMIDE

The same procedure as in Example 7, replacing 4-chlorobutyryl chlorideby bromoacetyl chloride.

EXAMPLE 10N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

0.01 mol of morpholine is dissolved with magnetic stirring in 50 cm³ ofacetone. 0.012 mol of triethylamine and 0.01 mol ofN-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-bromoacetamide are added.The mixture is brought to reflux for one hour with magnetic stirring.The precipitate formed is drained and the filtrate is evaporated. Theresidue is taken up with alkaline water. The precipitate is drained,washed, dried and recrystallized.

Infrared Spectrometry

1760 cm⁻¹, νCO(O--CO--N)

EXAMPLE 11N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-{4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}ACETAMIDE

Using the procedure described in the preceding example, but replacingmorpholine by 1-[(2,3,4-trimethoxyphenyl)methyl]piperazine, the productof the title is obtained.

EXAMPLE 12 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-N-METHYLACETAMIDE

By replacing 2-(6-methoxy-3-benzoxazolinonyl)-ethylamine in Example 1 byN-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-N-methylamine, the product ofthe title is obtained.

EXAMPLE 13 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]BENZAMIDE

By replacing acetyl chloride in Example 1, stage C, by benzoyl chloride,the product of the title is obtained.

Infrared Spectrometry

1760 cm⁻¹, νCO

EXAMPLE 14N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

By replacing acetyl chloride in Example 1, stage C, by para-toluoylchloride, the product of the title is obtained.

Infrared Spectrometry

1760 cm⁻¹, νCO

EXAMPLE 15 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-4-FLUOROBENZAMIDE

By replacing acetyl chloride in Example 1, stage C, bypara-fluorobenzoyl chloride, the product of the title is obtained.

Infrared Spectrometry

1765 cm⁻¹, νCO

EXAMPLE 16

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

By replacing acetyl chloride in Example 1, stage C, by3-(trifluoromethyl)benzoyl chloride, the product of the title isobtained.

Infrared Spectrometry

1760 cm⁻¹, νCO

EXAMPLE 17N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

By replacing acetyl chloride in Example 1, stage C, by3,5-dichlorobenzoyl chloride, the product of the title is obtained.

EXAMPLE 18 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]ISONICOTINAMIDE

By replacing acetyl chloride in Example 1, stage C, by isonicotinoylchloride, the product of the title is obtained.

EXAMPLE 19 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-INDOLECARBOXAMIDE

By replacing acetyl chloride in Example 1, stage C, by 2-indolecarbonylchloride, the product of the title is obtained.

Infrared Spectrometry

3400 cm⁻¹, νNH (indole)

1760 cm⁻¹, νCO

EXAMPLE 20N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

Using the procedure described in Example 10, and replacing morpholine bybenzylamine, the product of the title is obtained.

Infrared Spectrometry

1760 cm⁻¹, νCO

EXAMPLE 21N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-(N',N'-DIETHYLAMINO)ACETAMIDE

Using the procedure described in Example 10, but replacing morpholine byN,N-diethylamine, the product of the title is obtained.

Infrared Spectrometry

1765 cm⁻¹, νCO (OCON)

EXAMPLE 22 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-AMINOACETAMIDEHYDROCHLORIDE

0.012 mol of hexamethylenetetramine is dissolved with magnetic stirringin 15 cm³ of chloroform, and 0.01 mol ofN-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-bromoacetamide, obtained inExample 9, dissolved in 20 cm³ of chloroform, is introduced. The mixtureis brought to reflux for 100 hours. The product is drained and dried.The precipitate is introduced into a ground-necked flask. 150 cm³ ofalcohol and 30 cm³ of concentrated hydrochloric acid are added.

The mixture is brought to reflux for 2 hours. The solvent is evaporatedoff. The product is recrystallized in 90° strength alcohol.

Infrared Spectrometry

1760 cm⁻¹, νCO (OCON)

EXAMPLE 23N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL]ACETAMIDE

Using the procedure described in Example 10, but replacing morpholine by1-(4-fluorophenyl)piperazine, the product of the title is obtained.

EXAMPLE 24N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-{4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

Using the procedure described in Example 10, but replacing morpholine by1-[3-(trifluoromethyl)phenyl]-piperazine, the product of the title isobtained.

EXAMPLE 25N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE (R₂=cyclohexyl)

Using the procedure described in Example 1, but replacing acetylchloride by cyclohexanecarbonyl chloride, the product of the title isobtained.

EXAMPLE 26 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]FORMAMIDE

0.01 mol of 2-(6-methoxy-3-benzoxazolinonyl)-ethylamine and 0.02 mol offormic acid are placed in a porcelain crucible. The mixture is heated to120° C. until a dry residue is obtained. The product is recrystallized.

EXAMPLE 27N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

Using the procedure described in Example 1, but replacing acetylchloride by cyclopropanecarbonyl chloride, the product of the title isobtained.

EXAMPLE 28 N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]PENTANAMIDE

Using the procedure described in Example 1, but replacing acetylchloride by valeroyl chloride, the product of the title is obtained.

EXAMPLE 29N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

Using the procedure described in Example 1, but replacing acetylchloride by cyclobutanecarbonyl chloride, the product of the title isobtained.

Using the procedure described in the preceding examples, the followingare likewise obtained:

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-4-BROMOBUTYRAMIDE

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-5-BROMOPENTANAMIDE

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-3-BROMOPROPIONAMIDE

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-3-MORPHOLINOPROPIONAMIDE

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-4-MORPHOLINOBUTYRAMIDE

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-4-{4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}-BUTYRAMIDE

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-3-(4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}-PROPIONAMIDE

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-PIPERIDONE

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-BROMOPROPIONAMIDE

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-(4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}-PROPIONAMIDE

By replacing 2-(6-methoxy-3-benzoxazolinonyl)ethyamine in Examples 5 to9 by 2-(5-methoxy-3-benzoxazolinonyl)ethylamine, the products of thepreceding examples methoxylated, respectively, at position 5 of thebenzoxazolinone are obtained instead of the compounds methoxylated atposition 6.

EXAMPLE 30 N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]ACETAMIDE STAGE A:(6-METHOXY-3-BENZOTHIAZOLINONYL)ACETONITRILE

The procedure used is that described in Example 1, stage A, replacing6-methoxybenzoxazolinone by 6-methoxybenzothiazolinone.

Recrystallization solvent: 95° strength alcohol

Yield: 93%.

Melting point: 168-169° C.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 54.52        3.66   12.72                                         Found:      54.59        3.52   12.73                                         ______________________________________                                        Infrared spectrometry:                                                        (3080-2940) cm.sup.-1, ν C--H                                              1680 cm.sup.-1, ν CO(S--CO--N)                                             (1630-1580) cm.sup.-1, ν C═C (aromatic)                                Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         3.85 ppm, (s, 3H), OCH.sub.3                                                  4.75 ppm, (s, 2H), CH.sub.2 --CN                                              6.75 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.5                            7.30 ppm, (d, 1H), H.sub.7                                                    ______________________________________                                    

STAGE B 2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYLAMINE HYDROCHLORIDE

The procedure used is that described in Example 1, stage B, replacing(6-methoxy-3-benzoxazolinonyl)-acetonitrile by(6-methoxy-3-benzothiazolinonyl)acetonitrile obtained in stage A.

Recrystallization solvent: 95° strength alcohol/water (5:1).

Yield: 83%.

Melting point:>260° C.

    ______________________________________                                                Infrared spectrometry:                                                ______________________________________                                                (3120-2500) cm.sup.-1, ν NH.sub.2 salt                                     1640 cm.sup.-1, ν CO(S--CO--N)                                             1600 cm.sup.-1, ν C═C (aromatic)                               ______________________________________                                    

STAGE C: N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]ACETAMIDE

The procedure used is that described in Example 1, stage C, replacing2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride by2-(6-methoxy-3-benzothiazolinonyl(ethylamine hydrochloride obtained instage B.

Recrystallization solvent: Toluene.

Yield: 80%.

Melting point: 152-154° C.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 54.11        5.29   10.52                                         Found:      54.19        5.32   10.43                                         ______________________________________                                        Infrared spectrometry:                                                        3240 cm.sup.-1, ν N--H                                                     (3060-2840) cm.sup.-1, ν C--H                                              1675 cm.sup.-1, ν CO(S--CO--N)                                             1650 cm.sup.-1, ν CO (amide)                                               1580 cm.sup.-1, ν C═C (aromatic)                                       Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         1.94 ppm, (s, 3H), COCH.sub.3                                                 3.80 ppm, (s, 3H), OCH.sub.3                                                  6.10 ppm, (signal, 1H), NH                                                    6.80 ppm, (dd, 1H), H.sub.5                                                   7.00 ppm, (d, 1H), H.sub.7                                                    7.20 ppm, (d, 1H), H.sub.4                                                    ______________________________________                                    

EXAMPLE 31 N-[2-(5-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]ACETAMIDE STAGE A(5-METHOXY-3-BENZOTHIAZOLINONYL)ACETONITRILE

The procedure used is that described in Example 1, stage A, replacing6-methoxybenzoxazolinone by 5-methoxybenzothiazolinone.

Recrystallization solvent: 95° strength alcohol.

Yield: 93%.

Melting point: 154-156° C.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 54.52        3.66   12.72                                         Found:      54.88        3.47   12.76                                         ______________________________________                                        Infrared spectrometry:                                                        (3080-2940) cm.sup.-1, ν C--H                                              1680 cm.sup.-1, ν CO(S--CO--N)                                             (1630-1580) cm.sup.-1, ν C═C (aromatic)                                Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         3.85 ppm, (s, 3H), OCH.sub.3                                                  4.75 ppm, (s, 2H), CH.sub.2 --CN                                              6.75 ppm, (unresolved peaks, 2H), H.sub.4, H.sub.6                            7.30 ppm, (d, 1H), H.sub.7                                                    ______________________________________                                    

STAGE B 2-(5-METHOXY-3-BENZOTHIAZOLINONYL)ETHYLAMINE HYDROCHLORIDE

The procedure used is that described in Example 1, stage B, replacing(6-methoxy-3-benzoxazolinonyl)acetonitrile by(5-methoxy-3-benzothiazolinonyl)acetonitrile obtained in stage A.

Recrystallization solvent: 95° strength alcohol

Yield: 86%.

Melting point:>260° C.

    ______________________________________                                        Infrared spectrometry:                                                        (3100-2500) cm.sup.-1, ν NH.sub.2 salt                                     1640 cm.sup.-1, ν CO(S--CO--N)                                             1590 cm.sup.-1, ν C═C (aromatic)                                       Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         3.75 ppm, (s, 3H), OCH.sub.3                                                  6.80 ppm, (dd, 1H), H.sub.6                                                   7.25 ppm, (d, 1H), H.sub.4                                                    7.50 ppm, (d, 1H), H.sub.7                                                    8.50 ppm, (signal, 2H), NH.sub.2 disappears in D.sub.2 O                      ______________________________________                                    

STAGE C N-[2-(5-METHOXY-3-BENZOTHIAZLINONYL)ETHYL]ACETAMIDE

The procedure used is that described in Example 1, stage B, replacing2-(6-methoxy-3-benzoxazolinonyl)-ethylamine hydrochloride by2-(5-methoxy-3-benzothiazolinonyl)ethylamine hydrochloride obtained instage B.

Recrystallization solvent: Toluene.

Yield: 86%.

Melting point: 120-122° C.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 54.11        5.29   10.52                                         Found:      54.42        5.28   10.49                                         ______________________________________                                        Infrared spectrometry:                                                        3280 cm.sup.-1, ν NH amide                                                 (3080-2840) cm.sup.-1, ν CH                                                1675 cm.sup.-1, ν CO(SCON)                                                 1650 cm.sup.-1, ν CO (amide)                                               1610 cm.sup.-1, ν CC (aromatic)                                            Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         1.93 ppm, (s, 3H), COCH.sub.3                                                  ##STR34##                                                                    3.80 ppm, (s, 3H), OCH.sub.3                                                   ##STR35##                                                                    6.10 ppm, (signal, 1H), NH                                                    6.75 ppm, (dd, 1H), H.sub.6                                                   6.90 ppm, (d, 1H), H.sub.4                                                    7.30 ppm, (d, 1H), H.sub.7                                                    ______________________________________                                    

EXAMPLE 32 N-[2-(5-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]ISOBUTYRAMIDE

The procedure used is that described in Example 31, replacing acetylchloride in stage C by isobutyryl chloride.

Recrystallization solvent: Toluene/cyclohexane.

Yield: 87%.

Melting point: 158-159° C.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 57.12        6.16   9.51                                          Found:      57.14        6.07   9.33                                          ______________________________________                                        Infrared spectrometry:                                                        3280 cm.sup.-1, ν NH                                                       (3080-2840) cm.sup.-1, ν CH                                                1675 cm.sup.-1, ν CO(SCON)                                                 1640 cm.sup.-1, ν CO (amide)                                               1600 cm.sup.-1, ν CC (aromatic)                                            Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         1.10 ppm, (s, 6H), CH(CH.sub.3).sub.2                                         2.25 ppm, (multiplet, 1H), CH                                                  ##STR36##                                                                    3.85 ppm, (s, 3H), OCH.sub.3                                                   ##STR37##                                                                    6.15 ppm, (signal, 1H), NH                                                    6.70 ppm, (dd, 1H), H.sub.6                                                   6.80 ppm, (d, 1H), H.sub.4                                                    7.26 ppm, (d, 1H), H.sub.7                                                    ______________________________________                                    

EXAMPLE 33 N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]ISOBUTYRAMIDE

The procedure used is that described in Example 31, replacing acetylchloride in stage C by isobutyryl chloride.

Recrystallization solvent: Toluene/cyclohexane.

Yield: 85%

Melting point: 136-138° C.

    ______________________________________                                        Elemental analysis:                                                                       C %          H %    N %                                           ______________________________________                                        Calculated: 57.12        6.16   9.51                                          Found:      57.44        6.35   9.72                                          ______________________________________                                        Infrared spectrometry:                                                        3300 cm.sup.-1, ν NH                                                       (3080-2840) cm.sup.-1, ν CH                                                1680 cm.sup.-1, ν CO(SCON)                                                 1640 cm.sup.-1, ν CO (amide)                                               1600 cm.sup.-1, ν CC (aromatic)                                            Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                          ##STR38##                                                                    2.25 ppm, (multiplet, 1H), CH                                                 3.80 ppm, (s, 3H), OCH.sub.3                                                  6.10 ppm, (signal, 1H), NH                                                    6.85 ppm, (dd, 1H), H.sub.5                                                   7.00 ppm, (d, 1H), H.sub.7                                                    7.20 ppm, (d, 1H), H.sub.4                                                    ______________________________________                                    

EXAMPLES 34 TO 58

Using the procedure described in Examples 5 to 29, but replacing2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride in stage C by2-(6-methoxy-3-benzothiazolinonyl)ethylamine hydrochloride, thefollowing are obtained, respectively:

EXAMPLE 34

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]PHENYLACETAMIDE

EXAMPLE 35

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE

EXAMPLE 36

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)-4-CHLOROBUTYRAMIDE

EXAMPLE 37

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-2-PYRROLIDINONE

EXAMPLE 38

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-2-BROMOACETAMIDE

EXAMPLE 39

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

EXAMPLE 40

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-2-(4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL)ACETAMIDE

EXAMPLE 41

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-N-METHYLACETAMIDE

EXAMPLE 42

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]BENZAMIDE

EXAMPLE 43

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

EXAMPLE 44

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-4-FLUOROBENZAMIDE

EXAMPLE 45

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

EXAMPLE 46

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

EXAMPLE 47

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]ISONICOTINAMIDE

EXAMPLE 48

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-2-INDOLECARBOXAMIDE

EXAMPLE 49

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

EXAMPLE 50

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-2-(N',N'-DIETHYLAMINO)ACETAMIDE

EXAMPLE 51

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-2-AMINOACETAMIDE

EXAMPLE 52

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL]ACETAMIDE

EXAMPLE 53

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]-2-(4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 54

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE

EXAMPLE 55

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]FORMAMIDE

EXAMPLE 56

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

EXAMPLE 57

N-[2-(6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]VALERAMIDE

EXAMPLE 58

N-[2-{6-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

By replacing 2-(6-methoxy-3-benzothiazolinonyl)ethylamine in Examples 34to 58 by 2-(5-methoxy-3-benzothiazolinonyl)ethylamine, the products ofthe preceding examples methoxylated, respectively, at position 5 areobtained instead of the compounds methoxylated at position 6.

EXAMPLE 59

N-[2-(6-METHOXY-4-BENZOXAZINONYL)ETHYL]ACETAMIDE

By replacing 6-methoxybenzoxazolinone in Example 1, stage A, by6-methoxybenzoxazinone, the following are obtained, respectively:

STAGE A

2-(6-METHOXY-4-BENZOXAZINONYL)ACETONITRILE

STAGE B

2-(6-METHOXY-4-BENZOXAZINONYL)ETHYLAMINE HYDROCHLORIDE

STAGE C

N-[3-(6-METHOXY-3-BENZOXAZINONYL)ETHYL]ACETAMIDE

EXAMPLE 60

N-[2-(7-METHOXY-4-BENZOXAZINONYL)ETHYL]ACETAMIDE

Using the procedure described in Example 1, but replacing6-methoxybenzoxazolinone by 7-methoxybenzoxazinone, the following areobtained, respectively:

2-(7-METHOXY-4-BENZOXAZINONYL)ACETONITRILE

2-(7-METHOXY-4-BENZOXAZINONYL)ETHYLAMINE HYDROCHLORIDE

N-[2-(7-METHOXY-4-BENZOXAZINONYL)ETHYL]ACETAMIDE

EXAMPLE 61 N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]ACETAMIDE

0.02 mol of 2-(3-methyl-6-benzoxazolinonyl)-ethylamine hydrochloridedescribed in Patent Application EP 0,110,781, is dissolved in awater/chloroform mixture. 0.02 mol of potassium carbonate is added andthe mixture is left stirring for one hour.

It is cooled in an ice bath and 0.022 mol of acetyl chloride is thenadded. The mixture is kept stirring for 30 minutes. The chloroform phaseis washed with water, dried over calcium chloride and taken to dryness.The residue is recrystallized in toluene.

Yield: 76%.

Melting point: 150° C.

    ______________________________________                                        Infrared spectrometry:                                                        2260 cm.sup.-1, ν NH                                                       (3080-2880) cm.sup.-1, ν CH                                                1775 cm.sup.-1, ν CO(O--CON)                                               1640 cm.sup.-1, ν CO (amide)                                               1615 cm.sup.-1, ν CC (aromatic)                                            Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         1.96 ppm, (s, 3H), COCH.sub.3                                                  ##STR39##                                                                    3.43 ppm, (s, 3H), NCH.sub.3                                                   ##STR40##                                                                    5.60 ppm, (signal, 1H), NH                                                    6.80 ppm, (d, 1H), H.sub.4                                                    7.00 ppm, (unresolved peaks, 2H), H.sub.5, H.sub.7                            ______________________________________                                    

EXAMPLE 62 N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]ACETAMIDE

By replacing 2-(3-methyl-6-benzoxazolinonyl)-ethylamine hydrochloride inExample 61 by 2-(3-methyl-6-benzothiazolinonyl)ethylamine hydrochloride,described in French Patent Application 90/11,866, the product of thetitle is obtained

Yield: 79%.

Melting point: 134-136° C.

    ______________________________________                                        Infrared spectrometry:                                                        3280 cm.sup.-1, ν NH                                                       (3080-2860) cm.sup.-1, ν CH                                                1670 cm.sup.-1, ν CO(SCON)                                                 1630 cm.sup.-1, ν CO (amide)                                               1600 cm.sup.-1, ν CC (aromatic)                                            Nuclear Magnetic Resonance Spectrometry (CDCl.sub.3):                         1.96 ppm, (s, 3H), COCH.sub.3                                                  ##STR41##                                                                     ##STR42##                                                                    5.50 ppm, (signal, 1H), NH                                                    6.95 ppm, (d, 1H), H.sub.4                                                    7.20 ppm, (unresolved peaks, 2H), H.sub.5, H.sub.7                            ______________________________________                                    

EXAMPLE 63 N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]ISOBUTYRAMIDE

Using the procedure described in Example 61, but replacing acetylchloride by isobutyryl chloride, the product of the title is obtained.

    ______________________________________                                                 Infrared spectrometry:                                               ______________________________________                                                 1760 cm.sup.-1, ν CO (OCON)                                                1640 cm.sup.-1, ν CO (amide)                                      ______________________________________                                    

EXAMPLE 64 N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]PHENYLACETAMIDE

Using the procedure described in Example 61, but replacing acetylchloride by phenacetyl chloride, the product of the title is obtained.

EXAMPLE 65N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE##STR43##

The procedure used is that described in Example 6, replacing3-(2-aminoethyl)-6-methoxybenzoxazolinone by2-(3-methyl-6-benzoxazolinonyl)ethylamine; the product of the title isobtained.

EXAMPLES 66 TO 88

Using the procedure described in Examples 7 to 29, but replacing2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride by2-(3-methyl-6-benzoxazolinonyl)ethylamine hydrochloride, the followingare obtained:

EXAMPLE 66

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-4-CHLOROBUTYRAMIDE

EXAMPLE 67

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-2-PYRROLIDINONE

EXAMPLE 68

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]2-BROMOACETAMIDE

EXAMPLE 69

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

EXAMPLE 70

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-2-(4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 71

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-N-METHYLACETAMIDE

EXAMPLE 72

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]BENZAMIDE

EXAMPLE 73

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

EXAMPLE 74

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-4-FLUOROBENZAMIDE

EXAMPLE 75

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

EXAMPLE 76

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

EXAMPLE 77

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]ISONICOTINAMIDE

EXAMPLE 78

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-2-INDOLECARBOXAMIDE

EXAMPLE 79

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

EXAMPLE 80

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-2-(N,,N,-DIETHYLAMINO)ACETAMIDE

EXAMPLE 81

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-2-AMINOACETAMIDE

EXAMPLE 82

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL]ACETAMIDE

EXAMPLE 83

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]-2-{4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 84

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE

EXAMPLE 85

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]FORMAMIDE

EXAMPLE 86

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

EXAMPLE 87

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]VALERAMIDE

EXAMPLE 88

N-[2-(3-METHYL-6-BENZOXAZOLINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

EXAMPLES 89 TO 113

Using the procedure described in Examples 5 to 20, but replacing2-(6-methoxy-3-benzoxazolinonyl)-ethylamine hydrochloride by2-(3-methyl-6-benzothiazolinonyl)ethylamine hydrochloride, the followingare obtained:

EXAMPLE 89

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]PHENYLACETAMIDE

EXAMPLE 90

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE

EXAMPLE 91

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-4-CHLOROBUTYRAMIDE

EXAMPLE 92

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-2-PYRROLIDINONE

EXAMPLE 93

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-2-BROMOACETAMIDE

EXAMPLE 94

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

EXAMPLE 95

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-2-{4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 96

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-N-METHYLACETAMIDE

EXAMPLE 97

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]BENZAMIDE

EXAMPLE 98

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

EXAMPLE 99

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-4-FLUOROBENZAMIDE

EXAMPLE 100

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

EXAMPLE 101

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

EXAMPLE 102

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]ISONICOTINAMIDE

EXAMPLE 103

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-2-INDOLECARBOXAMIDE

EXAMPLE 104

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

EXAMPLE 105

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-2-(N',N'-DIETHYLAMINO)ACETAMIDE

EXAMPLE 106

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-2-AMINOACETAMIDE

EXAMPLE 107

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL]ACETAMIDE

EXAMPLE 108

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]-2-{4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 109

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE

EXAMPLE 110

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]FORMAMIDE

EXAMPLE 111

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

EXAMPLE 112

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]VALERAMIDE

EXAMPLE 113

N-[2-(3-METHYL-6-BENZOTHIAZOLINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

By replacing 2-(3-methyl-6-benzothiazolinonyl)-ethylamine in Examples 89to 113 by 2-(3-methyl-7-benzothiazolinonyl)ethylamine, obtained inPatent Application EP 174,811, products are obtained which are isomericwith those above, the side chain being at position 7 instead of atposition 6:

EXAMPLE 114

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]PHENYLACETAMIDE

EXAMPLE 115

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE

EXAMPLE 116

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-4-CHLOROBUTYRAMIDE

EXAMPLE 117

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-2-PYRROLIDINONE

EXAMPLE 118

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-2-BROMOACETAMIDE

EXAMPLE 119

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

EXAMPLE 120

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]2-(4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 121

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-N-METHYLACETAMIDE

EXAMPLE 122

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]BENZAMIDE

EXAMPLE 123

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

EXAMPLE 124

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-4-FLUOROBENZAMIDE

EXAMPLE 125

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

EXAMPLE 126

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

EXAMPLE 127

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]ISONICOTINAMIDE

EXAMPLE 128

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-2-INDOLECARBOXAMIDE

EXAMPLE 129

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

EXAMPLE 130

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-2-(N',N'-DIETHYLAMINO)ACETAMIDE

EXAMPLE 131

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-2-AMINOACETAMIDE

EXAMPLE 132

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL]ACETAMIDE

EXAMPLE 133

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]-2-(4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 134

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE

EXAMPLE 135

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]FORMAMIDE

EXAMPLE 136

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

EXAMPLE 137

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]VALERAMIDE

EXAMPLE 138

N-[2-(3-METHYL-7-BENZOTHIAZOLINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

EXAMPLES 139 TO 162

Using the procedure described in Examples 5 to 26, but replacing2-(6-methoxy-3-benzoxazolinonyl)-ethylamine hydrochloride in stage C by2-(4-methyl-7-benzoxazinonyl)ethylamine hydrochloride, the following areobtained, respectively:

EXAMPLE 139

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]PHENYLACETAMIDE

EXAMPLE 140

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE

EXAMPLE 141

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-4-CHLOROBUTYRAMIDE

EXAMPLE 142

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-2-PYRROLIDINONE

EXAMPLE 143

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-2-BROMOACETAMIDE

EXAMPLE 144

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

EXAMPLE 145

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-2-(4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 146

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-N-METHYLACETAMIDE

EXAMPLE 147

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]BENZAMIDE

EXAMPLE 148

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

EXAMPLE 149

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-4-FLUOROBENZAMIDE

EXAMPLE 150

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

EXAMPLE 151

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

EXAMPLE 152

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]ISONICOTINAMIDE

EXAMPLE 153

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-2-INDOLECARBOXAMIDE

EXAMPLE 154

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

EXAMPLE 155

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-2-(N',N'-DIETHYLAMINO)ACETAMIDE

EXAMPLE 156

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-2-AMINOACETAMIDE

EXAMPLE 157

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL)ACETAMIDE

EXAMPLE 158

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]-2-{4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 159

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE

EXAMPLE 160

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]FORMAMIDE

EXAMPLE 161

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

EXAMPLE 162

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]VALERAMIDE

EXAMPLE 163

N-[2-(4-METHYL-7-BENZOXAZINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

Using the procedure described in Examples 5 to 29, but replacing2-(6-methoxy-3-benzoxazolinonyl)ethylamine hydrochloride in stage C by2-(4-methyl-6-benzoxazinonyl)ethylamine hydrochloride, described inPatent Application FR 90/11,866 the following are obtained:

EXAMPLE 164

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]PHENYLACETAMIDE

EXAMPLE 165

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE

EXAMPLE 166

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-4-CHLOROBUTYRAMIDE

EXAMPLE 167

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-2-PYRROLIDINONE

EXAMPLE 168

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-2-BROMOACETAMIDE

EXAMPLE 169

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

EXAMPLE 170

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-2-(4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 171

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-N-METHYLACETAMIDE

EXAMPLE 172

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]BENZAMIDE

EXAMPLE 173

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

EXAMPLE 174

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-4-FLUOROBENZAMIDE

EXAMPLE 175

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

EXAMPLE 176

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

EXAMPLE 177

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]ISONICOTINAMIDE

EXAMPLE 178

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-2-INDOLECARBOXAMIDE

EXAMPLE 179

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

EXAMPLE 180

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-2-(N',N'-DIETHYLAMINO)ACETAMIDE

EXAMPLE 181

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-2-AMINOACETAMIDE

EXAMPLE 182

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL]ACETAMIDE

EXAMPLE 183

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]-2-{4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

EXAMPLE 184

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE

EXAMPLE 185

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]FORMAMIDE

EXAMPLE 186

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

EXAMPLE 187

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]VALERAMIDE

EXAMPLE 188

N-[2-(4-METHYL-6-BENZOXAZINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

EXAMPLE 189

N-[2-(6-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-METHYLCYCLOPROPANECARBOXAMIDE

R₂ =2-METHYLCYCLOPROPYL

Using the procedure described in Example 1, but replacing acetylchloride in stage C by 2-methylcyclopropanecarbonyl chloride, theproduct of the title is obtained.

EXAMPLE 190N-[2-(5-METHOXY-3-BENZOXAZOLINONYL)ETHYL]-2-METHYLCYCLOPROPANECARBOXAMIDE

Using the procedure described in Example 189, but replacing6-methoxybenzoxazolinone in stage A by 5-methoxybenzoxazolinone, theproduct of the title is obtained.

EXAMPLE 191N-[2-(5-METHOXY-3-BENZOXAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

Using the procedure described in Example 1, but replacing6-methoxybenzoxazolinone in stage A by 5-methoxybenzoxazolinone, andacetyl chloride by cyclopropanecarbonyl chloride, the product of thetitle is obtained.

Recrystallization: toluene

Melting point: 150-151° C.

EXAMPLE 192

N-[2-(5-METHOXY-3-BENZOTHIAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

Using the procedure described in Example 1, but replacing6-methoxybenzoxazolinone in stage A by 5-methoxy-benzothiazolinone, andacetyl chloride by cyclopropanecarbonyl chloride, the product of thetitle is obtained.

Recrystallization: toluene

Melting point: 135-136° C.

Using the procedure described in Examples 1 and 4 to 29, but replacing6-methoxybenzoxazolinone by benzoxazolinone itself, the following areobtained:

N-[2-(3-BENZOXAZOLINONYL)ETHYL]ACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]ISOBUTYRAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]PHENYLACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-4-CHLOROBUTYRAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-PYRROLIDINONE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-BROMOACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-(4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}ACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-N-METHYLACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]BENZAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-4-FLUOROBENZAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL]ACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]ISONICOTINAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-INDOLECARBOXAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-(N',N'-DIETHYLAMINO)ACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-AMINOACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-(4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]FORMAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]VALERAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

Using the procedure described in Examples 1 and to 29, but replacing6-methoxybenzoxazolinone by benzothiazolinone, the following areobtained:

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]ACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]ISOBUTYRAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]PHENYLACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-4-CHLOROBUTYLAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-PYRROLIDINONE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-BROMOACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-{4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}ACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-N-METHYLACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]BENZAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-4-FLUOROBENZAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL]ACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]ISONICOTINAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-INDOLECARBOXAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-(N',N'-DIETHYLAMINO)ACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-AMINOACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-{4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]FORMAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]VALERAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

Using the procedure described in Examples 61 to 88, but replacing3-methylbenzoxazolinone by benzoxazolinone itself, the following areobtained:

N-[2-(6-BENZOXAZOLINONYL)ETHYL]ACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]ISOBUTYRAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]PHENYLACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-4-CHLOROBUTYRAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-2-PYRROLIDINONE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-2-BROMOACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

N-[2-(3-BENZOXAZOLINONYL)ETHYL]-2-{4-[2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}ACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-N-METHYLACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]BENZAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-4-FLUOROBENZAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL]ACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]ISONICOTINAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-2-INDOLECARBOXAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-2-(N',N'-DIETHYLAMINO)ACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-2-AMINOACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]-2-(4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]FORMAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]VALERAMIDE

N-[2-(6-BENZOXAZOLINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

Using the procedure described in Examples 61 to 88, but replacing3-methylbenzoxazolinone by benzothiazolinone itself, the following areobtained

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]ACETAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]ISOBUTYAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]PHENYLACETAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-(2-OXO-1-PYRROLIDINYL)ACETAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-4-CHLOROBUTYLAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-2-PYRROLIDINONE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-2-BROMOACETAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-2-MORPHOLINOACETAMIDE

N-[2-(3-BENZOTHIAZOLINONYL)ETHYL]-2-(4-[(2,3,4-TRIMETHOXYPHENYL)METHYL]-1-PIPERAZINYL}ACETAMAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-N-METHYLACETAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]BENZAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-PARA-TOLUENECARBOXAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-4-FLUOROBENZAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-2-[4-(4-FLUOROPHENYL)-1-PIPERAZINYL]ACETAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-3-(TRIFLUOROMETHYL)BENZAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-3,5-DICHLOROBENZAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]ISONICOTINAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-2-INDOLECARBOXAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-2-(BENZYLAMINO)ACETAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-2-(N',N'-DIETHYLAMINO)ACETAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-2-AMINOACETAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]-2-{4-[3-(TRIFLUOROMETHYL)PHENYL]-1-PIPERAZINYL}ACETAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]CYCLOHEXANECARBOXAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]FORMAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]CYCLOPROPANECARBOXAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]VALERAMIDE

N-[2-(6-BENZOTHIAZOLINONYL)ETHYL]CYCLOBUTANECARBOXAMIDE

PHARMACOLOOGICAL STUDY OF THE COMPOUNDS OF THE INVENTION EXAMPLE A:STUDY OF ACUTE TOXICITY

Acute toxicity was assessed after oral administration to batches of 8mice (26±2 grams). The animals were observed at regular intervals duringthe first day and daily during the two weeks following treatment. TheLD₅₀ causing the death of 50% of the animals was evaluated.

The LD₅₀ of the products tested is greater than 1000 mg.kg⁻¹ for most ofthe compounds studied, which indicates the low toxicity of the compoundsof the invention.

EXAMPLE B: ACTIVITY MEASUREMENT

The animals are placed in plexiglass boxes equipped with photoelectriccells placed in a darkened environment. Six animals are testedsimultaneously, and the number of interruptions of the photoelectricbeams by each animal is recorded by computer during one hour.

The test compounds are administered intraperitoneally immediately beforeplacing the animals in the apparatus.

The products of the invention decrease the animals' activity.

EXAMPLE C: FOUR PLATES TEST

The products of the invention are administered via the esophagus tobatches of ten mice. One batch receives acacia syrup.

30 minutes after administration of the test products, the animals areplaced in compartments the floor of which comprises four metal plates.Every time the animal passes from one plate to another, it receives amild electric shock (0.35 mA). The number of transfers from one plate toanother is recorded during one minute. After administration, thecompounds of the invention significantly increase the number oftransfers from one plate to another, demonstrating the anxiolyticactivity of the compounds of the invention.

EXAMPLE D: ACTIVITY OF THE PRODUCTS OF THE INVENTION IN RELATION TOISCHEMIC MICROCIRCULATION

The experimental study was carried out on the cremaster muscles of malerats (Sprague-Dawley) after ligation of the common iliac artery.

The muscles were placed in a transparent chamber perfused with abicarbonate buffer solution equilibrated with a 5:95% CO₂ /N₂ gaseousmixture. The velocity of the red cells and the diameter of the first orsecond order arterioles irrigating the cremaster were measured, and thearteriolar blood flow was calculated. Identical data were obtained forfour types of venules.

The same type of measurement was made simultaneously:

on the normally perfused cremaster,

on the ligated cremaster, that is to say the ischemic cremaster, 2, 7,14 and 21 days after ligation.

Two group of animals were studied:

an untreated control group,

a group treated orally with a product of the invention at the rate of0.1 mg.kg⁻¹ per day.

No difference was noted in the velocity of the red cells or in thediameter of the vessels in the normally irrigated cremaster muscles inthe treated animals in comparison to the controls.

In contrast, in the ischemic cremaster muscle, the mean diameter of thearterioles was improved in the treated animals in comparison to thecontrols. The velocity of the red cells was normalized by treatment for21 days.

In fact, in the treated animals, the velocity of the red cells and theblood flow measured 7 days after ligation show no significant differencefrom the values obtained in the non-ischemic cremaster. These resultsare obtained without modification of arterial blood pressure.

These results indicate that long-term treatment with a compound of theinvention improves the microcirculation and irrigation with blood ofischemic areas.

EXAMPLE E: STIMULATION OF THE IMMUNE RESPONSE

Batches of six mice were administered sheep red cells. These batches ofmice were then treated subcutaneously with the compounds of theinvention for six days, and a control group was treated with a placebo.The mice were then left undisturbed for four weeks and thereafterreceived a booster injection of sheep red cells without receivingfurther administrations of a product of the invention. The immuneresponse was evaluated 3 days after the booster injection. Itstatistically increased in the group treated with the compounds of theinvention.

EXAMPLE F: INHIBITION OF OVULATION

Adult female rats with regular four-day cycles were used.

Daily vaginal smears were prepared, and rats were selected after showingat least two consecutive four-day cycles.

Each cycle consists of two days of diestrus, one day of proestrus andone day of estrus.

In the afternoon of the day of proestrus, luteinizing hormone isreleased into the blood by the pituitary. This hormone inducesovulation, which results in the presence of ova in the oviduct on theday of estrus.

The compounds of the invention are on set orally at midday on the day ofestrus. The treated and control rats are sacrificed on the day ofestrus. The oviducts are examined. A significant percentage decrease inthe number of ova is noted in the oviducts of treated rats.

EXAMPLE G: DEMONSTRATION OF ANALGESIC ACTIVITY

The activity against pain was investigated in mice (23-25 g) accordingto a protocol derived from the technique described by SIEGMUND (SIEGMUNDE.A., R.A. CADMUS & GOLU, J. Pharm. Exp. Ther. 119, 1874, 1954). Mice,randomized in batches of 12 animals, received the treatment orally(excipient in the case of controls) 1 hour before intraperitonealinjection of a 0.02% aqueous-alcoholic solution of phenyl-p-benzoquinone(Sigma). The writhing movements are counted between the 5th and 10thminute after injection

It was apparent that some compounds of the invention possess analgesicactivity.

EXAMPLE H: POTENTIATION OF BARBITURATE-INDUCED SLEEP

Mice (22-25 g) are injected intraperitoneally with pentobarbital at 50mg.kg⁻¹. The time of onset and the duration of sleep are measured. Theanimals are taken to be asleep when they lose the righting reflex. Thetest compounds are administered intraperitoneally 30 minutes before thebarbiturate injection. The products of the invention increase theduration of pentobarbital-induced sleep.

EXAMPLE I: TEST OF BINDING TO MELATONIN RECEPTORS

Binding of the compounds of the invention to melatonin receptors wascarried out according to conventional techniques. It is apparent thatthe compounds of the invention bind beneficially to melatonin receptors.

EXAMPLE J: STUDY OF HYPOGLYCEMIC ACTIVITY

Male KK mice were placed in cages at the age of eight weeks. They areused for the experiment when their weight is greater than 40 grams atthe age of 4-5 months.

The compound of the invention is suspended in acacia syrup. Eachcompound tested is administered orally 18 hours before blood sampling.

Blood is collected by sampling from the caudal vein in a hematocrittube, and then centrifuged. The plasma is collected and the blood sugarlevel assayed.

It is apparent that some compounds of the invention significantlydecrease the blood sugar level.

EXAMPLE K: STUDY OF THE INFLUENCE OF THE PRODUCTS OF THE INVENTION ONMELATONIN SYNTHESIS

The products of the invention are administered intraperitoneally to rats(Sprague-Dawley) at doses 1, 5 and 25 mg.kg⁻¹. Three hours afteradministration, the animals are sacrificed and melatonin assayedradioimmunologically. The measurement is validated by performingparallel controls. A considerable increase is observed in the plasmamelatonin level after administration of the products of the invention.

EXAMPLE L: PHARMACEUTICAL COMPOSITION: TABLETS

Tablets containing 30 mg ofN-[2-(3-methyl-6-benzoxazolinonyl)ethyl]acetamide

    ______________________________________                                        N-[2-(3-Methyl-6-benzoxazolinonyl)ethyl]acetamide                                                        30     g                                           Wheat starch               15     g                                           Corn starch                15     g                                           Lactose                    15     g                                           Magnesium stearate         2      g                                           Silica                     1      g                                           Hydroxypropylcellulose     2      g                                           ______________________________________                                    

We claim:
 1. A compound of selected from those formula (I): ##STR44## inwhich: A represents an oxygen or sulfur,X represents a single bond, Rrepresents:hydrogen or lower alkyl, and in this case p=1 and Brepresents --CH₂ --CH₂ --NR₁ --CO--R₂ where R₁ represents hydrogen orlinear or branched lower alkyl,and R₂ represents: a group of theformula: ##STR45## G representing linear or branched lower alkyl and R₃and R₄, together with the nitrogen atom to which they are attached, forma piperazino group optionally substituted with one or more lower alkyl,oxo, phenyl or pheny (lower alkyl), or substituted phenyl or substitutedphenyl (lower alkyl), in the definitions of R₃ and R₄, the term"substituted" qualifying phenyl and phenyl (lower alkyl) meaning thatthese groups are substituted with one or more radicals chosen from loweralkyl, lower alkoxy, trifluoromethyl and halogen, or R represents (CH₂)₂--NR₁ --CO--R₂ with R₁ and R₂ having the same definition as given above,and in which case p equals 0 or 1 and B represents lower alkoxy, and itsisomers, epimers and diastereoisomers as well as, its addition saltswith a pharmaceutically-acceptable acid or base, lower alkyl and loweralkoxy having 1 to 6 carbon atoms inclusive and cycloalkyl having 3 to 8carbon atoms inclusive.
 2. A compound as claimed in claim 1 in which Rrepresents (CH₂)₂ --NR₁ --CO--R₂, B represents methoxy, and p represents1, its isomers as well as, where appropriate, its addition salts with apharmaceutically-acceptable acid.
 3. A compound as claimed in claim 1which isN-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-{4-[(2,3,4-trimethoxyphenyl)methyl]-1-piperazinyl}acetamide.4. A compound as claimed in claim 1 which isN-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-[4-(4-fluorophenyl)-1-piperazinyl]acetamide.5. A compound as claimed in claim 1 which isN-[2-(6-methoxy-3-benzoxazolinonyl)ethyl]-2-{4-[3-(trifluoromethyl)phenyl]-1-piperazinyl}acetamide.6. A pharmaceutical composition containing as active principal acompound as claimed in claim 1 in combination with a pharmaceuticallyacceptable excipient or vehicle.
 7. A method for treating a livinganimal afflicted with a sleep disorder, comprising the step ofadministering to the said living animal an amount of a compound of claim1 which is effective for alleviation of the said condition.